Process for preparation of 3,5-bisalkylphenols

ABSTRACT

The invention provides a process for producing a 3,5-bisalkylphenol (2) according to the following reaction scheme:  
                 
 
     (wherein R 1  represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or a hydroxyl-protecting group (other than methyl group); R 2  represents a C1 to C5 lower alkyl group or an optionally substituted phenyl group; and each of R 3  and R 4 , which may be identical to or different from each other, represents a lower alkyl group, an aralkyl group, or an aryl group); a carbinol compound (1); and a process for producing the carbinol compound. The production process of the present invention enables efficient and safe production of a variety of 3,5-bisalkylphenols including 3,5-diisopropylphenol, which are important as synthesis intermediates for drugs and agricultural chemicals, in shorter steps at high purity in high yield, thus contributing to consistent supply of drugs and agricultural chemicals.

TECHNICAL FIELD

[0001] The present invention relates to a process for producing3,5-diisopropylphenol or a similar compound, which serves as anintermediate for producing anti-inflammatory agents, pesticides, etc.;to a carbinol compound for use in production of the phenol compound; andto a process for producing the carbinol compound.

BACKGROUND ART

[0002] 3,5-Diisopropylphenol is an essential synthesis intermediate forproducing, for example, pyridine derivatives (WO 99/24404) serving asanti-inflammatory agents, as well as carbamate derivatives (JapanesePatent Application Laid-Open (kokai) No. 51-112519) serving aspesticides.

[0003] Conventionally, 3,5-diisopropylphenol is produced through any ofa variety of synthesis processes employing 1,3-diisopropylbenzene as astarting material. Such processes include those represented by thefollowing known synthesis schemes a and b:

[0004] (Journal of Organic Chemistry Vol. 36, p. 193-196 (1971)) and

[0005] (Journal of Organic Chemistry Vol. 32, p. 585-588 (1967)).

[0006] However, syntheses performed through any of these two schemeshave drawbacks. For example, when synthesis scheme a is employed,cumbersome purification steps are required and overall yield is low(approximately 45%). Although synthesis scheme b includes only twosteps, introduction of an amino group by use of trichloroamine, which istoxic and explosive, performed in the first step raises a problem interms of safety, and low yield as low as 8% is another problem.

[0007] Japanese Patent Application Laid-Open (kokai) No. 61-152635 andU.S. Pat. No. 2,790,010 disclose a two-step process for synthesizing3,5-diisopropylphenol employing 1,3,5-triisopropylbenzene as a startingmaterial as shown in the following synthesis scheme c.

[0008] Although overall yield reaches 56%, synthesis scheme c also hasdrawbacks such as transformation to a toxic, explosive peroxideintermediate having poor stability and requirement of rectification foryielding a final product. Accordingly, synthesis schemes a to c havebeen unsuitable for synthesizing 3,5-diisopropylphenol on a large scale.

[0009] In addition to synthesis schemes a to c, there have been reportedrelated synthesis methods including alkylation of a phenol species byuse of propene (Japanese Patent Application Laid-Open (kokai) Nos.46-6018 and 54-61131). However, the methods are not practical, sinceselectivity and yield are poor, and formed isomers are difficult toseparate from one another.

DISCLOSURE OF THE INVENTION

[0010] Thus, an object of the present invention is to provide a processfor producing 3,5-bisalkylphenol of high purity, which process comprisesa small number of steps and attains high production efficiency and yieldwith high safety.

[0011] In view of the foregoing, the present inventors have carried outextensive studies on a process suitable for producing 3,5-bisalkylphenolon a large scale, and have found that 3,5-bisalkylphenol can be producedat high yield through a two-step or three-step process employing a novelcarbinol compound as an intermediate which is obtained by alkylating anisophthalate ester derivative. The present invention has beenaccomplished on the basis of this finding.

[0012] Accordingly, the present invention provides a process, as shownin the following reaction scheme:

[0013] [wherein R¹ represents a hydrogen atom, an alkali metal atom, analkaline earth metal atom, or a hydroxyl-protecting group (other thanmethyl group); R² represents a C1 to C5 lower alkyl group or anoptionally substituted phenyl group; and each of R³ and R⁴, which may beidentical to or different from each other, represents a lower alkylgroup, an aralkyl group, or an aryl group], for producing3,5-bisalkylphenol (2), characterized by comprising reacting anisophthalate ester derivative represented by formula (3) with a metallicalkylating agent, to thereby form a carbinol compound represented byformula (1) (step-1), and subsequently, hydrogenolyzing the carbinolcompound and, in accordance with needs, removing the hydroxyl-protectinggroup (step-2).

[0014] The present invention also provides a carbinol compoundrepresented by formula (1) shown in the above reaction scheme.

[0015] The present invention also provides a process for producing3,5-bisalkylphenol (2) characterized by comprising hydrogenolyzing acarbinol compound represented by formula (1) shown in the above reactionscheme and, in accordance with needs, removing the hydroxyl-protectinggroup.

[0016] The present invention also provides a process for producing acarbinol compound represented by formula (1) characterized by comprisingreacting an isophthalate ester derivative represented by formula (3)shown in the above reaction scheme with a metallic alkylating agent.

BEST MODE FOR CARRYING OUT THE INVENTION

[0017] In the present invention, examples of preferred alkali metalatoms, represented by R¹ in formula (1) or (3), include lithium, sodium,and potassium. Examples of preferred alkaline earth metal atoms includecalcium and magnesium.

[0018] No particular limitation is imposed on the species of thehydroxyl-protecting group, represented by R¹, so long as the groupprotects hydroxyl group so as to prevent decrease in solubility of thecorresponding compound due to formation of a metal salt through reactionof the hydroxyl group with an metallic alkylating agent and the group iscaused to leave during hydrogenolysis or through a known method such asacid or alkali treatment.

[0019] Examples of groups which leave during hydrogenolysis includebenzyl, trityl, benzhydryl, p-methoxybenzyl, benzyloxymethyl, andbenzyloxycarbonyl. Examples of groups which do not leave duringhydrogenolysis but do leave through acid treatment, alkali treatment, oranother treatment include acetal type protecting groups such asmethoxymethyl, tetrahydropyranyl, and methoxyethoxymethyl; alkyl groupssuch as ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, andn-pentyl; alkenyl groups such as allyl; alkynyl groups such aspropargyl; aralkyl groups such as 1-phenylethyl, 1-phenylpropyl, and2-phenylpropyl; silyl groups such as triethylsilyl,t-butyldimethylsilyl, and t-butyldiphenylsilyl; sulfonyl groups such asp-toluenesulfonyl, and methanesulfonyl; acyl groups such as acetyl,benzoyl, propionyl, butyryl, and isobutyryl; carbonate ester groups suchas methoxycarbonyl, ethoxycarbonyl, t-butyloxycarbonyl, andtrichloroethoxycarbonyl; p-bromophenacyl group; and phenylcarbamoylgroup.

[0020] Of these, groups which leave during hydrogenolysis are preferablyemployed, since hydrogenolysis of carbinol hydroxyl group anddeprotection of hydroxyl group are simultaneously performed.

[0021] R² represents a C1 to C5 lower alkyl group or an optionallysubstituted phenyl group. Examples of preferred C1 to C5 lower alkylgroups include methyl, ethyl, n-propyl, isopropyl, n-butyl, andn-pentyl. Of these, methyl and ethyl are more preferred, with methylbeing particularly preferred.

[0022] Examples of optionally substituted phenyl groups include phenylgroups mono-substituted or di-substituted by a lower alkoxy group, alower alkyl group, a halogen atom, a lower alkylthio group, or a similargroup. Specific examples of optionally substituted phenyl groups includephenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,bromophenyl, iodophenyl, and methylthiophenyl.

[0023] Examples of lower alkyl groups, represented by R³ or R⁴, includeC1 to C7 linear or branched alkyl groups. Specific examples includemethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, n-pentyl,isopentyl, n-hexyl, isohexyl, n-heptyl, and isoheptyl. Of these, C1 toC5 alkyl groups are preferred, with methyl being particularly preferred.

[0024] Examples of aralkyl groups, represented by R³ and R⁴, aralklygroups having a C1 to C3 alkyl moiety. Specific examples includephenyl-(C1 to C3) alkyl groups such as benzyl, 1-phenylethyl,1-phenylpropyl, and 2-phenylpropyl. Of these, benzyl is particularlypreferred.

[0025] Examples of aryl groups, represented by R³ and R⁴, includephenyl, naphthyl, and phenyl or naphthyl group having a substituent suchas methyl or methoxy.

[0026] The steps of the production process according to the presentinvention will next be described in detail.

[0027] Step-1

[0028] The carbinol compound (1) can be produced by reacting anisophthalate ester derivative (3) with a metallic alkylating agent.

[0029] Examples of the metallic alkylating agent include Grignardreagents such as methylmagnesium bromide, ethylmagnesium bromide,propylmagnesium bromide, isopropylmagnesium bromide, butylmagnesiumbromide, pentylmagnesium bromide, phenylmagnesium bromide,methylmagnesium chloride, and methylmagnesium iodide; Grignard reagentsprepared from activated magnesium; organometallic reagents such asmethyllithium and butyllithium; and organometallic reagents containing arare earth element (e.g., samarium) such as a reagent prepared from analkyl halide and samarium iodide. Of these, methylmagnesium bromide ispreferred.

[0030] Preferably, the metallic alkylating agent is used in an amount of4 to 8 equivalents based on the isophthalate ester derivative (3).

[0031] No particular limitation is imposed on the reaction solvent solong as the solvent can dissolve starting compounds and does not inhibitformation of a target compound. Examples include tetrahydrofuran,diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, toluene,and benzene. Of these, tetrahydrofuran is preferred. In addition, asolubilizing aid such as tetramethylethylenediamine orhexamethylphosphoramide is preferably added to the solvent. Furthermore,Lewis acid such as trifluoroboron-diethyl ether complex, titaniumtetrachloride, cerium chloride, or trimethylaluminum; and analkylammonium salt such as tetrabutylammonium bromide may be added tothe solvent.

[0032] The reaction is performed at 0 to 100° C. in a nitrogen or argonatmosphere for 3 to 10 hours under moisture-free conditions.Particularly, the reaction is preferably performed in tetrahydrofuranfor 3 to 6 hours under reflux conditions.

[0033] After completion of reaction, acid such as dilute hydrochloricacid or dilute sulfuric acid or an aqueous saturated ammonium chloridesolution is added to the reaction mixture, and the mixture is extractedwith an organic solvent, to thereby yield a carbinol compound (1).

[0034] In Step-1, a ketone compound (4) shown below may be by-producedas an impurity. Such an impurity can be removed by subjecting a crudeextract to adsorption treatment by use of sulfonylhydrazine resin.

[0035] Specifically, after completion of alkylation, a crude product isdissolved in an organic solvent such as methanol, 1,2-dichloroethane,1,2-dimethoxyethane, acetonitrile, or tetrahydrofuran, preferably inmethanol, and sulfonylhydrazine resin is added to the resultantsolution. The formed ketone compound (4) can be adsorbed by thesulfonylhydrazine resin by shaking the mixture at room temperature to100° C., preferably at room temperature to 50° C. The thus-obtainedreaction mixture is subjected to filtration, to thereby obtain ahigh-purity carbinol compound (1) from which the ketone compound (4) isremoved. The time required for the reaction can be remarkably shortenedby adding acetic acid in an amount of 5% (V/V) to the aforementionedsolvent such as dichloromethane, 1,2-dichloroethane,1,2-dimethoxyethane, acetonitrile, or tetrahydrofuran and shaking themixture at room temperature.

[0036] The sulfonylhydrazine resin used in the present invention can beproduced by transforming a starting resin (e.g., poly(styrenesulfonicacid) resin) to the corresponding resin. Specifically, a styrenesulfonylresin prepared from Amberlyst A-15 (product of Rohm & Haas) inaccordance with a method described in Journal of Organic Chemistry Vol.44, p. 4634 (1979)) or a commercially availablepoly(styrenesulfonylhydrazine) resin (product of Argonaut) is preferablyused.

[0037] By performing reaction of step-2 after removal of the ketonecompound in a manner as described above, 3,5-bisalkylphenol containingno ketone-derived substance can be obtained, leading to enhancement inpurity.

[0038] Among isophthalate ester derivatives (3) serving as a startingsubstance, a compound (R¹=a hydroxyl-protecting group) can be obtainedby protecting, through a routine method, the hydroxyl group of acommercially available 5-hydroxyisophthalate diester derivative.

[0039] Step-2

[0040] 3,5-Bisalkylphenol (2) can be produced by hydrogenolyzing acarbinol compound (1) and, in accordance with need, removing ahydroxyl-protecting group.

[0041] Hydrogenolysis of step-2 can be performed through any ofcustomary processes. For example, there can be employed (i) ahydrogenolysis method including dissolving a carbinol compound (1) in anorganic solvent such as ethanol, isopropyl alcohol, or n-butanol andadding concentrated hydrochloric acid to the solution in the presence ofa catalyst such as palladium-carbon, palladium black, palladiumhydroxide, or platinum oxide, preferably in the presence ofpalladium-carbon at room temperature to refluxing temperature or (ii)the Birch's reduction employing liquid ammonia and sodium.

[0042] When R¹ is a hydroxyl-protecting group which can leave duringhydrogenolysis; e.g., benzyl, trityl, benzhydryl, p-methoxybenzyl,benzyloxymethyl, or benzyloxycarbonyl, the protecting group is removedduring hydrogenolysis, to thereby form a 3,5-bisalkylphenol (2). When ahydroxyl-protecting group which is difficult to leave during theaforementioned hydrogenolysis is employed, deprotection is performedthrough acid treatment, alkali treatment, or other known means afterperformance of hydrogenolysis.

[0043] The acid treatment or alkali treatment is performed, for example,in an alcoholic solvent such as methanol, ethanol, or butanol; a mixtureof water and the alcoholic solvent; or a mixture of water andtetrahydrofuran, dioxian, or a similar solvent. Examples of acidsemployed in the acid treatment include inorganic acids such ashydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, andhydroiodic acid; organic sulfonic acids such as methanesulfonic acid andp-toluenesulfonic acid; and organic carboxylic acids such as acetic acidand oxalic acid. Examples of alkali compounds used in the alkalitreatment include alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide; alkali metal carbonates such as sodium carbonateand potassium carbonate; metal alkoxides such as sodium methoxide andsodium ethoxide; and organic bases such as piperidine and morpholine. Inaddition to acid treatment or alkali treatment, treatment with Lewisacid such as aluminum trichloride or boron tribromide may be employed.

[0044] The target compound can be isolated through a purification methodgenerally employed in the field of organic synthesis; e.g., filtration,washing, drying, recrystallization, and a variety of chromatographicmethods.

EXAMPLES

[0045] The present invention will next be described in more detail byway of examples.

Referential Example 1 Synthesis of Dimethyl 5-benzyloxyisophthalate

[0046] To a solution of dimethyl 5-hydroxyisophthalate (50.0 g, 238mmol) in N,N-dimethylformamide (500 mL), benzyl bromide (29.5 mL, 248mmol) was added dropwise in the presence of potassium carbonate (42.4 g,307 mmol), and the reaction mixture was stirred for 2 hours at roomtemperature, followed by addition of water thereto. The resultantmixture was extracted with diethyl ether. The resultant organic layerwas washed sequentially with water and saturated brine and dried oversodium sulfate anhydrate. The solvent was removed under reducedpressure, to thereby yield a solid. The solid was crystallized fromdiethyl ether, to thereby yield 68.9 g of dimethyl5-benzyloxyisophthalate as colorless needles (yield 96%).

[0047] Melting point: 96-97° C.

[0048] IR(KBr)cm⁻¹: 3420, 2955, 1721, 1596, 1501, 1460.

[0049]¹H-NMR (CDCl₃)δ: 3.94(6H,s), 5.15(2H,s), 7.33-7.46(5H,m),7.84(2H,s), 8.30(1H,s).

[0050] EIMS m/z: 300(M⁺), 91(100)

[0051] Elementary analysis: as C₁₇H₁₆O₅

[0052] Calculated: C, 67.99; H, 5.37

[0053] Found: C, 68.01; H, 5.48

Example 1 Synthesis of5-benzyloxy-α,α,α′,α′-tetramethyl-1,3benzenedimethanol

[0054] Under argon atmosphere, dimethyl 5-benzyloxyisophthalate (28.6 g,95.2 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (100 mL),and a 12% (W/V) solution (520 mL) of methylmagnesium bromide (523.3mmol) in anhydrous THF was added dropwise to the solution underice-cooling. The mixture was refluxed for 3 hours. After cooling thereaction mixture, methanol, water, and 1N HCl were added to the reactionmixture, and the resultant mixture was extracted with chloroform. Theresultant organic layer was washed sequentially with water and saturatedbrine and dried over sodium sulfate anhydrate. The solvent was removedunder reduced pressure, to thereby yield a solid residue.

[0055] The thus-obtained residue was dissolved in methanol (1,200 mL),and poly(styrenesulfonylhydrazine) resin (37.3 g, 100.3 mmol) was addedto the solution. The resultant mixture was shaken at room temperaturefor 36 hours. The reaction mixture was subjected to filtration, and thefiltrate was concentrated under reduced pressure, to thereby yieldcrystals. The crystals were recrystallized from hexane-chloroform, tothereby yield 26.6 g of5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol as colorlessneedles (yield 93%).

[0056] Melting point: 146-147° C.

[0057] IR(KBr)cm⁻¹: 3474, 3267, 2976, 1592, 1429, 1364.

[0058]¹H-NMR(CDCl₃)δ: 1.58(12H,s), 5.08(2H,s), 7.02(2H,s), 7.22(1H,s),7.33(1H,t,J=7. Hz), 7.39(2H,t,J=7. Hz), 7.45(2H,d,J=7. Hz).

[0059] EIMS m/z: 300(M⁺), 91(100)

[0060] Elementary analysis: as C₁₉H₂₄O₃

[0061] Calculated: C, 75.97; H, 8.05

[0062] Found: C, 75.92; H, 8.04

Example 2 Synthesis of 3,5-diisopropylphenol

[0063] To a solution of5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol (22.9 g, 76mmol) in ethanol (500 mL), concentrated hydrochloric acid (2.6 mL) and a10% palladium-carbon catalyst (8.0 g) were added. Under hydrogenatmosphere, the mixture was stirred for 23 hours at 60° C. The reactionmixture was subjected to filtration, and the filtrate was concentratedunder reduced pressure, to thereby yield 13.6 g of 3,5-diisopropylphenolas a solid (yield 100%). The solid was crystallized from hexane, tothereby yield colorless needles.

[0064] Melting point: 51-52° C.

[0065] IR(KBr)cm⁻¹: 3307, 2961, 2926, 2869, 1618, 1595.

[0066]¹H-NMR(CDCl₃)δ: 1.22(12H,d,J=7.0 Hz), 2.83(2H,sept,J=7. Hz),6.53(2H,s), 6.67(1H,s)

[0067] EIMS m/z: 178(M⁺), 163(100)

Example 3 Synthesis of5-hydroxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol

[0068] Under argon atomosphere, a 12% (W/V) solution (969 mL) ofmethylmagnesium bromide (975.0 mmol) in anhydrous THF was added dropwiseto a solution of dimethyl 5-hydroxyisophthalate (31.5 g, 150.0 mmol) inanhydrous THF (1,500 mL) under ice-cooling. After addition was complete,the reaction mixture was refluxed for 3 hours. After cooling themixture, an aqueous saturated ammonium chloride solution was added tothe reaction mixture, to thereby deactivate the residual Grignardreagent. Subsequently, water and 1N HCl were sequentially added fordilution, followed by extraction with ethyl acetate. The resultantorganic layer was washed sequentially with water and saturated brine anddried over sodium sulfate. The solvent was removed under reducedpressure, to thereby yield a solid residue. The thus-obtained residuewas dissolved in methanol (1,500 mL), and poly(styrenesulfonylhydrazine)resin (90.3 g, 285.3 mmol) was added to the solution. The resultantmixture was shaken for 24 hours at room temperature, and the resin wasremoved through filtration. The filtrate and methanol used for washingwere combined, and the combined liquid was concentrated under reducedpressure, to thereby yield a white solid. The thus-obtained solid wascrystallized from hexane-diethyl ether, to thereby yield 20.6 g of5-hydroxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol as colorlessneedles (yield 65.3%).

[0069] Melting point: 137-138° C.

[0070] IR(KBr)cm⁻¹: 3358, 3227, 2973, 1606, 1503, 1432.

[0071]¹H-NMR(CDCl₃)δ: 1.57(12H,s), 6.88(2H,s), 7.15(1H,s).

[0072] EIMS m/z: 210(M⁺), 177(100)

[0073] Elementary analysis: as C₁₂H₁₈O₃

[0074] Calculated: C, 68.55, H, 8.63

[0075] Found: C, 68.40, H, 8.52

Example 4 Synthesis of 3,5-diisopropylphenol

[0076] To a solution of5-hydroxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol (20.0 g, 95.1mmol) in ethanol (600 mL), concentrated hydrochloric acid (12.0 mL) anda 10% palladium-carbon catalyst (11.0 g) were added, and the mixture wasstirred under hydrogen atmosphere for 22 hours at room temperature. Thereaction mixture was subjected to filtration, and the filtrate wasconcentrated under reduced pressure, to thereby yield a white solid. Thethus-obtained solid was crystallized from hexane, to thereby yield 16.5g of 3,5-diisopropylphenol as colorless needles (yield 97.3%).

[0077] Melting point: 51-52° C.

[0078] IR(KBr)cm⁻¹: 3307, 2961, 2926, 2869, 1618, 1595

[0079]¹H-NMR(CDCl₃)δ: 1.22(12H,d,J=7.0 Hz), 2.83(2H,sept,J=7.0 Hz),6.53(2H,s), 6.67(1H,s).

[0080] EIMS m/z: 178(M⁺) 163(100)

Example 5 Synthesis of5-benzyloxy-α,α,α′,α′-tetraethyl-1,3-benzenedimethanol

[0081] The procedure (including reaction and treatment) of Example 1 wasrepeated, except that methylmagnesium bromide was replaced byethylmagnesium bromide, to thereby obtain the above-described target asa pale yellow oil.

[0082] IR(film)cm⁻¹: 3474, 2969, 2937, 2879, 1593, 1498.

[0083]¹H-NMR(CDCl₃)δ: 0.74(12H,t,J=7.4 Hz), 1.78(4H,dq,J=14.3, 7.4 Hz),1.85(4H,dq,J=14.3,7.4 Hz), 5.07(2H,s), 6.90(2H,s), 6.92(1H,s),7.31(1H,t,J=7.2 Hz), 7.38(2H,t,J=7.2 Hz), 7.45(2H,d,J=7.2 Hz).

Example 6 Synthesis of 3,5-bis(1-ethylpropyl)phenol

[0084] The procedure (including reaction and treatment) of Example 2 wasrepeated, except that5-benzyloxy-α,α,α′,α′tetramethyl-1,3-benzenedimethanol was replaced by5-benzyloxy-α,α,α′,α′-tetraethyl-1,3-benzenedimethanol, to thereby yieldthe above-described target as colorless needles.

[0085] IR(KBr)cm⁻¹: 3350, 2962, 2924, 2872, 1618, 1597.

[0086]¹H-NMR(CDCl₃)δ: 0.76(12H,t,J=7.4 Hz), 1.44-1.56(4H,m),1.58-1.70(4H,m),2.22(2H,t,J=9.2,5.3 Hz), 4.52(1H,s), 6.43(2H,s),6.48(1H,s).

Example 7 Synthesis of5-benzyloxy-α,α,α′,α′-tetrapropyl-1,3-benzenedimethanol

[0087] The procedure (including reaction and treatment) of Example 1 wasrepeated, except that methylmagnesium bromide was replaced byn-propylmagnesium bromide, to thereby yield the above-described targetas a pale yellow oil.

[0088] IR(film)cm⁻¹: 3470, 2958, 2934, 2872, 1593, 1498 .

[0089]¹H-NMR(CDCl₃)δ: 0.84(12H,t,J=7.3 Hz), 0.99-1.11(4H,m),1.21-1.34(4H,m), 1.72(4H,dt,J=14.1,5.1 Hz), 1.78(4H,dt,J=14.1,5.1 Hz),5.07(2H,s),6.88(2H,s),6.92(1H,s), 7.32(1H,t,J=7.2 Hz), 7.38(2H,t,J=7.2Hz),7.45(2H,d,J=7.2 Hz).

Example 8 Synthesis of 3,5-bis(1-propylbutyl)phenol

[0090] The procedure (including reaction and treatment) of Example 2 wasrepeated, except that5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol was replaced by5benzyloxy-α,α,α′,α′-tetrapropyl-1,3-benzenedimethanol, to thereby yieldthe above-described target as a pale yellow oil.

[0091] IR(film)cm⁻¹: 3348, 2957, 2929, 1617, 1595, 1502.

[0092]¹H-NMR(CDCl₃)δ: 0.83(12H,t,J=7.3 Hz), 1.08-1.22(8H,m),1.41-1.60(8H,m), 2.42(2H,t,J=9.4,5.7 Hz), 4.59(1H,br.s), 6.42(2H,s),6.48(1H,s).

Example 9 Synthesis of5-benzyloxy-α,α,α′α′-tetrabutyl-1,3-benzenedimethanol

[0093] The procedure (including reaction and treatment) of Example 1 wasrepeated, except that methylmagnesium bromide was replaced byn-butylmagnesium bromide, to thereby yield the above-described target ascolorless powdery crystals.

[0094] IR(KBr)cm⁻¹: 3466, 2957, 2933, 1609, 1594, 1499.

[0095]¹H-NMR(CDCl₃)δ: 0.82(12H,t,J=7.2 Hz), 0.92-1.07(4H,m),1.13-1.32(12H,m), 1.68-1.86(8H,m), 5.08(2H,s), 6.89(1H,s), 6.90(2H,s),7.31(1H,t,J=7.2 Hz), 7.38(2H,t,J=7.2 Hz), 7.45(2H,d,J=7.2 Hz).

Example 10 Synthesis of 3,5-bis(1-butylpentyl)phenol

[0096] The procedure (including reaction and treatment) of Example 2 wasrepeated, except that5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol was replaced by5-benzyloxy-α,α,a′,a′-tetrabutyl-1,3-benzenedimethanol, to thereby yieldthe above-described target as colorless needles.

[0097] IR(film)cm⁻¹: 3355, 2957, 2927, 1616, 1597.

[0098]¹H-NMR(CDCl₃)δ: 0.81(12H,t,J=7.3 Hz), 1.05-1.33(16H,m),1.43-1.63(8H,m), 2.37(2H,t,J=9.1,5.1 Hz), 4.52(1H,s), 6.42(2H,s), 6.47(1H,s).

Example 11 Synthesis of5-benzyloxy-α,α,α′,α′-tetraisopropyl-1,3-benzenedimethanol

[0099] The procedure (including reaction and treatment) of Example 1 wasrepeated, except that methylmagnesium bromide was replaced byisopropylmagnesium bromide, to thereby yield the above-described targetas a colorless oily substance.

[0100] IR(film)cm⁻¹: 3536, 2968, 2936, 1591, 1498.

[0101]¹H-NMR(CDCl₃)δ: 0.76(12H,d,J=6.8 Hz), 0.83(12H,d,J=6.8 Hz),2.26(4H,sept,J=6.8 Hz), 5.08(2H,s), 6.91(1H,s), 6.94(2H,s),7.30(1H,t,J=7.3 Hz), 7.37(2H,t,J=7.3 Hz), 7.45(2H,d,J=7.3 Hz).

Example 12 3,5-Bis(1-isopropyl-2-methylpropyl)phenol

[0102] The procedure (including reaction and treatment) of Example 2 wasrepeated, except that5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol was replaced by5-benzyloxy-(α,α,α′,α′-tetraisopropyl-1,3-benzenedimethanol, to therebyyield the above-described target as a colorless oil.

[0103] IR(film)cm⁻¹: 3385, 2958, 2928, 1614, 1593, 1489.

[0104]¹H-NMR(CD₃OD)δ: 0.66(12H,d,J=6.6 Hz), 0.76(12H,d,J=6.6 Hz),1.88(2H,t,J=6.6 Hz), 1.99(4H,oct,J=6.6 Hz), 6.23(1H,s), 6.29(2H,s).

Example 13 Synthesis of5-benzyloxy-α,α,α′,α′-tetraphenyl-1,3-benzenedimethanol

[0105] The procedure (including reaction and treatment) of Example 1 wasrepeated, except that methylmagnesium bromide was replaced byphenylmagnesium bromide, to thereby yield the above-described target asa colorless oil.

[0106] IR(film)cm⁻¹: 3558, 3467, 3061, 3032, 1593, 1492.

[0107]¹H-NMR(CDCl₃)δ: 2.72(2H,br.s), 4.87(2H,s), 6.82(1H,s), 6.85(2H,s),7.17-7.33(25H,m).

Example 14 Synthesis of 3,5-dibenzhydrylphenol

[0108] The procedure (including reaction and treatment) of Example 2 wasrepeated, except that5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol was replaced by5benzyloxy-α,α, α′,α′-tetraphenyl-1,3-benzenedimethanol, to therebyyield the above-described target as a colorless oil.

[0109] IR(film)cm⁻¹: 3536, 3410, 3061, 3026, 1597, 1494.

[0110]¹H-NMR(CDCl₃)δ: 4.52(1H,br.s), 5.40(2H,s), 6.37(2H,s), 6.57(1H,s),7.05(8H,dd,J=8.3,1.5 Hz), 7.15-7.26(12H,m).

[0111] Industrial Applicability

[0112] The production process of the present invention enables efficientand safe production of a variety of 3,5-bisalkylphenols including3,5-diisopropylphenol, which are important as synthesis intermediatesfor drugs and agricultural chemicals, in shorter steps at high purity inhigh yield, thus contributing to consistent supply of drugs andagricultural chemicals.

1. A carbinol compound represented by the following formula (1):

(wherein R¹ represents a hydrogen atom, an alkali metal atom, analkaline earth metal atom, or a hydroxyl-protecting group (other thanmethyl group); and R² represents a C1 to C5 lower alkyl group or anoptionally substituted phenyl group).
 2. A process for producing a3,5-bisalkylphenol represented by the following formula (2):

(wherein R² represents a C1 to C5 lower alkyl group or an optionallysubstituted phenyl group) characterized by comprising hydrogenolyzing acarbinol compound represented by the following formula (1):

(wherein R¹ represents a hydrogen atom, an alkali metal atom, analkaline earth metal atom, or a hydroxyl-protecting group (other thanmethyl group); and R² has the same meaning as described above) and, inaccordance with needs, removing the hydroxyl-protecting group.
 3. Aprocess for producing a carbinol compound represented by the followingformula (1):

(wherein R¹ represents a hydrogen atom, an alkali metal atom, analkaline earth metal atom, or a hydroxyl-protecting group (other thanmethyl group); and R² represents a C1 to C5 lower alkyl group or anoptionally substituted phenyl group) characterized by comprisingreacting a metallic alkylating agent with an isophthalate esterderivative represented by the following formula (3):

(wherein R¹ has the same meaning as described above; and each of R³ andR⁴, which may be identical to or different from each other, represents alower alkyl group, an aralkyl group, or an aryl group).
 4. A process forproducing a carbinol compound as described in claim 3, which furtherincludes a treatment of adsorbing a by-product by use of asulfonylhydrazine resin.
 5. A process for producing a 3,5-bisalkylphenolrepresented by the following formula (2):

(wherein R ² represents a C1 to C5 lower alkyl group or an optionallysubstituted phenyl group) characterized by comprising reacting ametallic alkylating agent with an isophthalate ester derivativerepresented by the following formula (3):

(wherein R¹ represents a hydrogen atom, an alkali metal atom, analkaline earth metal atom, or a hydroxyl-protecting group (other thanmethyl group); and each of R³ and R⁴, which may be identical to ordifferent from each other, represents a lower alkyl group, an aralkylgroup, or an aryl group), to thereby form a carbinol compoundrepresented by the following formula (1):

(wherein each of R¹ and R² has the same meaning as described above)(step-1), and subsequently, hydrogenolyzing the carbinol compound and,in accordance with needs, removing the hydroxyl-protecting group(step-2).
 6. A process for producing a 3,5-bisalkylphenol as describedin claim 5, wherein the step-1 includes a treatment of adsorbing aby-product by use of a sulfonylhydrazine resin.
 7. A process forproducing a 3,5-bisalkylphenol as described in any one of claims 2, 5,and 6, wherein R² in formula (1) or (2) is a methyl group.